Pharmacological and analytical aspects of alkannin/shikonin and their derivatives: An update from 2008 to 2022

Alkannin/shikonin (A/S) and their derivatives are naturally occurring naphthoquinones majorly found in Boraginaceae family plants. They are integral constituents of traditional Chinese medicine Zicao (roots of Lithospermum erythrorhizon). In last two decades significant increase in pharmacological investigations on alkannin/shikonin and their derivatives has been reported that resulted in discovery of their novel mechanisms in various diseases and disorders. This review throws light on recently conducted pharmacological investigations on alkannin/shikonin and their derivatives and their outputs. Various analytical aspects are also discussed and brief summary of patent applications on inventions containing alkannin/shikonin and its derivatives is also provided.     

Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb–drug combination

Shikonin, a natural naphthoquinone compound derived from the herb Lithospermum erythrorhizon, is widely used for its various pharmacological activities. However, its potential interactions with other medications by inhibiting human carboxylesterases 2 (hCE2) remain unknown. In this study, the inhibitory effects of shikonin on the activity of hCE2 in human liver microsomes are investigated by using fluorescein diacetate (FD), N‐(2‐butyl‐1,3‐dioxo‐2,3‐dihydro‐1H‐phenalen‐6‐yl)‐2‐chloroacetamide (NCEN), and CPT‐11 as substrates of hCE2. The results demonstrate that shikonin significantly inhibits the activity of hCE2 when FD and NCEN are used as substrates, whereas the half inhibition concentration value of shikonin increased by 5–30 times when CPT‐11 was used as the substrate. The inhibition types of shikonin against hCE2 activity reflected by 3 substrates were all best fit to noncompetitive manners. In addition, shikonin was found to distinctly suppress endogenous hCE2 activity, characterized with attenuated fluorescence. Furthermore, for drugs metabolized by hCE2 with the similar binding sites with FD or NCEN, the estimated magnitudes of area under the curve variation were approximately 9–357% in the presence of shikonin. Also, the area under the curve of CPT‐11 could be increased by 1–14% following administration of shikonin. These findings have clear clinical implications for the combination of shikonin and hCE2‐metabolizing prodrugs.     

Studies on in vitro metabolism of shikonin

Shikonin is one of the active components isolated from the root of Arnebia euchrona (Royle) Johnst. It has been shown to possess significant antibacterial, antiinflammatory and antitumour activities and has been used clinically. In this paper, rat liver microsomes were incubated in vitro to study the metabolism of shikonin and a reverse‐phase high performance liquid chromatography/photodiode array detector (DAD) method was used to separate and detect the metabolites. The effects of several factors on the metabolism were investigated and the metabolic system was optimized. The main metabolites were purified by RP‐HPLC and their structures were determined by UV, ¹H‐NMR and MS. S‐1 was dihydroxylated shikonin, S‐2 was 2‐OH shikonin and S‐3 was 6‐OH or 7‐OH shikonin. Copyright © 1999 John Wiley & Sons, Ltd.     

Plants with traditional uses and activities,relevant to the management of Alzheimer's disease and other cognitive disorders

In traditional practices of medicine, numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases such as Alzheimer's disease (AD) and other memory related disorders. An ethnopharmacological approach has provided leads to identifying potential new drugs from plant sources, including those for memory disorders. There are numerous drugs available in Western medicine that have been directly isolated from plants, or are derived from templates of compounds from plant sources. For example, some alkaloids from plant sources have been investigated for their potential in AD therapy, and are now in clinical use (e.g. galantamine from Galanthus nivalis L. is used in the United Kingdom). Various other plant species have shown favourable effects in AD, or pharmacological activities indicating the potential for use in AD therapy. This article reviews some of the plants and their active constituents that have been used in traditional medicine, including Ayurvedic, Chinese, European and Japanese medicine, for their reputed cognitive-enhancing and antidementia effects. Plants and their constituents with pharmacological activities that may be relevant to the treatment of cognitive disorders, including enhancement of cholinergic function in the central nervous system, anti-cholinesterase (anti-ChE), antiinflammatory, antioxidant and oestrogenic effects, are discussed.     

Shikonin ameliorates cerulein-induced acute pancreatitis in mice

Ethnopharmacological relevance

Shikonin, a highly liposoluble naphthoquinone pigment isolated from the traditional medical herbs Lithospermum erythrorhizon (LE), was considered to exhibit an anti-inflammatory property. While the potential of shikonin to ameliorate acute pancreatitis (AP) is unknown. Our aim was to investigate the effects of shikonin in a murine model of cerulein-induced pancreatitis.

Materials and methods

AP was induced in mice by six intraperitoneal injection of cerulein (50 μg/kg) at hourly intervals. Vehicle or shikonin (50 mg/kg) was pretreated 2 h before the first cerulein injection. After 6 h, 9 h and 12 h of the first cerulein injection, the severity of acute pancreatitis was assessed by biochemistry, myeloperoxidase activity, histological grading, proinflammatory cytokines levels and nuclear factor kappa B (NF-κB) activity.

Results

Shikonin administration significantly reduced serum amylase and lipase activities, pancreatic histological scores, TNF-α, IL-1β, IL-6 levels, MPO activity and NF-κB activity.

Conclusion

Taken together, these results suggest that shikonin might protect against experimental pancreatitis by reducing release of inflammatory cytokines via inhibition of NF-κB activity. The therapeutic role of shikonin in AP needs further investigation.     

新疆紫草PAL,HMGR,PGT基因的过表达和RNA干扰载体的构建

新疆紫草Arnebia euchroma是药用紫草的主要来源,其最重要成分紫草素类化合物具有很高的药用和工业价值。研究采用GATEWAY技术,构建新疆紫草次生代谢关键酶基因PAL, HMGR, PGT的过表达载体和RNAi载体,为相关转基因株系的构建搭建好平台。新疆紫草次生代谢关键酶基因过表达和RNA干扰载体的构建,是基于遗传物质的遗传研究平台的搭建,对于次生代谢途径上基因功能验证和功能基因的挖掘提供了极大的便利,同时也填补了新疆紫草在转基因领域研究的空白,对于培育紫草素高产株系具有重要意义。     

紫草素及其衍生物抗肿瘤作用研究进展

紫草素是从草本植物紫草Arnebiae Radix中提取的一种具有抗炎、抗病毒、抗肿瘤、促伤口愈合等生物活性的萘醌类化合物。近年来,紫草素及其衍生物的抗肿瘤作用被广泛研究。从构效关系、抗肿瘤作用机制等方面综述近5年紫草素及其衍生物的抗肿瘤作用的研究进展,以期为紫草素类化合物的研究及利用提供参考。     

紫草宁脂质体质量控制和抑制HUVEC细胞VEGF基因表达的研究

目的探讨紫草宁脂质体的质量控制方法及其对HUVEC细胞VEGF基因表达水平的影响。方法采用大豆卵磷脂、胆固醇等膜材料将药物紫草宁包囊在脂质体中,对其外观大小、Zeta电位、含量、包封率进行质量控制,将紫草宁脂质体放置不同的环境中进行稳定性考察。采用Q—PCR技术研究紫草宁及其脂质体对HUVEC细胞VEGF基因水平的影响。结果紫草宁脂质体的颗粒小于220nm;Zeta电位大于30mv;三批样品含量为0．22g／L,0．21g／L,0．21g／L;包封率分别为51．50％,81．31％,96．72％;紫草宁脂质体在4℃环境下较为稳定。紫草宁及其脂质体对HUVEC细胞VEGF基因表达有下调作用。结论紫草宁及其脂质体通过抑制VEGF基因,从而抑制VEGF蛋白的表达,最终抑制血管新生。紫草宁脂质体的抑制作用较紫草宁弱,是脂质体中的紫草宁从中缓慢释放的结果。     

Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds

The roots and rhizomes of licorice (Glycyrrhiza) species have long been used worldwide as a herbal medicine and natural sweetener. Licorice root is a traditional medicine used mainly for the treatment of peptic ulcer, hepatitis C, and pulmonary and skin diseases, although clinical and experimental studies suggest that it has several other useful pharmacological properties such as antiinflammatory, antiviral, antimicrobial, antioxidative, anticancer activities, immunomodulatory, hepatoprotective and cardioprotective effects. A large number of components have been isolated from licorice, including triterpene saponins, flavonoids, isoflavonoids and chalcones, with glycyrrhizic acid normally being considered to be the main biologically active component. This review summarizes the phytochemical, pharmacological and pharmacokinetics data, together with the clinical and adverse effects of licorice and its bioactive components.     

Phytochemistry and Pharmacology of Phyllanthus niruri L.: A Review

Phyllanthus niruri, a typical member of family Euphorbiaceae, is a small annual herb found throughout the tropical and subtropical regions of both hemispheres. The genus Phyllanthus has been used in traditional medicine for its wide range of pharmacological activities like antimicrobial, antioxidant, anticancer, antiinflammatory, antiplasmodial, antiviral, diuretic and hepatoprotective. This review summarizes the information about morphological, biochemical, ethanobotanical, pharmacological, biological and toxicological activities with special emphasis on mechanism of anticancer activity of P. niruri. Gaps in previous studies such as taxonomic inconsistency of P. niruri, novel phytochemicals and their therapeutic properties, especially mechanisms of anticancerous activity and market products available, have been looked into and addressed. Scientific information related to 83 phytochemicals (including many novel compounds detected recently by the authors) has been provided in a very comprehensive manner. Copyright © 2017 John Wiley & Sons, Ltd.     

Recent progress in pharmacological research of propolis.

Propolis is a resinous hive product collected by honeybees from various plant sources. It is a popular folk medicine possessing a broad spectrum of biological activities. It has also been used as a health drink in various Asian, European and American countries. Several groups of researchers have focused their attention on the biological activity of propolis and its active principles. Many scientific articles are published every year in different international journals related to the pharmacological properties of propolis. This review article compiles recent findings (since 1995) on the pharmacological properties of propolis focusing on its antihepatotoxic, antitumour, antioxidative, antimicrobial and antiinflammatory properties. The possible mechanism of action of propolis as well as the active compounds are discussed.     

Andrographolide inhibits the tumour necrosis factor-α-induced upregulation of ICAM-1 expression and endothelial-monocyte adhesion

Andrographolide, a diterpene isolated from Andrographis paniculata, has been shown to have several biological activities including analgesic, antipyretic and antiinflammatory effects. Since the upregulation of adhesion molecules expression and endothelial-leucocytes adhesion are key steps in the development of inflammation, the present study examines whether andrographolide modulates these biological processes in vitro. Incubation of endothelial cells with non-toxic concentrations (0.16–16.7 υg/mL) of andrographolide attenuated the tumour necrosis factor-α (TNF)-induced intercellular adhesion molecule-1 (ICAM-1) expression. Similar concentration ranges of andrographolide also inhibited the TNF-induced endothelial-monocyte adhesion in a concentration-dependent manner. These effects of andrographolide may account for its reported in vivoantiinflammatory activity. © 1998 John Wiley & Sons, Ltd.     

Biologically active sesquiterpene coumarins from Ferula species

Extracts from different species of the genus Ferula (Apiaceae) have had various biomedical applications for many centuries. Many biological features of this genus such as cytotoxicity, antibacterial, antiviral, P-glycoprotein (P-gp) inhibitory and antiinflammatory activity have been attributed to sesquiterpene coumarins; structures containing a common coumarin group and a sesquiterpene moiety. This both highlights the importance of sesquiterpene coumarins as biologically active natural products and necessitates further studies on these compounds. Taking into account the versatile biological properties of compounds isolated from Ferula and the unprecedented interest in the application of natural products as a new generation of therapeutics, the present review will discuss reports on biological activities of sesquiterpene coumarins of the genus Ferula, from 1990 onwards.     

Phytochemistry and Medicinal Properties of Teucrium polium L. (Lamiaceae)

Teucrium polium L. (family Lamiaceae) is a wild‐growing flowering plant, found abundantly in South‐Western Asia, Europe and North Africa. Traditionally, T. polium has been used for different pathological conditions such as gastrointestinal disorders, inflammations, diabetes and rheumatism. In traditional Iranian medicine (TIM), the tea of T. polium is used for treating many diseases such as abdominal pain, indigestion, common cold and type 2 diabetes. Based on this background, many studies have been followed for scientific confirmation of the above‐mentioned properties. In this review, 100 articles published from 1970 to 2011 in the area of phytochemistry, pharmacology and toxicology of extracts and compounds isolated from T. polium have been evaluated. During the past 40 years, different classes of compounds have been isolated from various parts of T. polium of which the main groups are terpenoids and flavonoids. It has been found that these compounds possess a broad spectrum of pharmacological effects including antioxidant, anticancer, antiinflammatory, hypoglycemic, hepatoprotective, hypolipidemic, antibacterial and antifungal. The results of data analyses on the chemical, pharmacological and toxicological characteristics of T. polium support the view that this plant has beneficial therapeutic properties. However, further studies to identify the active components and further verify their relevant pharmacological activities are warranted. Copyright © 2012 John Wiley & Sons, Ltd.     

Growth inhibition and induction of apoptosis in human oral squamous cell carcinoma Tca-8113 cell lines by Shikonin was partly through the inactivation of NF-kappaB pathway

Shikonin, a naphthoquinone pigment isolated from the Chinese herbal therapeutic, Zicao, has been shown to exhibit antioxidant and anticancer effects. In this study, its ability to induce apoptosis in cultured Tca-8113 oral cancer cells was studied. Treatment of the Tca-8113 cells with a variety of concentrations of Shikonin (10-40 microm) resulted in dose- and time-dependent sequences of events marked by apoptosis, as shown by the loss of cell viability, chromatin condensation, internucleosomal DNA fragmentation and sub-G1 phase accumulation. Furthermore, apoptosis in the Tca-8113 cells was accompanied by the activation of protease caspase-8, -9, -3 and low expression of Bcl-2 protein. Interestingly, inactivation of the NF-kappaB pathway was found in shikonin-induced apoptosis in Tca-8113 cells. These results raise the possibility that the anti-tumor effects of Shikonin in Tca-8113 cells are at least partly through the inactivation of the NF-kappaB pathway and subsequent activation of protease caspase family. Pharmacological inhibition of the NF-kappaB activity by Shikonin might be a powerful treatment option for OSCC in which activation of NF-kappaB plays a critical role in tumor growth and progression.     

Suppression of croton oil-induced rabbit corneal edema by sideritis javalambrensis

This investigation was designed to evaluate the anti-inflammatory activity of the aqueous and hexane extracts of Sideritis javalambrensis, to which pharmacological properties have been attributed in Spanish traditional medicine. The extracts were applied as eye drops in a croton oil-induced corneal edema model in rabbits. Corneal thickness was estimated before the induction of inflammation and 3, 6, 8, 12, 48, 72 and 96 h after induction. Significant inflammation inhibition percentages were shown during both the acute and chronic stages of inflammation by both extracts and by the reference drug dexamethasone, with most therapeutic effect shown during the chronic phase. However, the hexane extract exhibited potent anti-inflammatory activity from 6 to 24 h post-induction, achieving greater percentage inhibition values during this stage than those obtained for dexamethasone.     

Pharmacological investigations of Hibiscus micranthus Linn., a febrifuge used in Saudi Arabian folk medicine

The ethanolic extract of Hibiscus micranthus Linn. has been studied for its pharmacological activities. It has been found to produce significant inhibition of carrageenan induced paw oedema and cotton pellet induced granuloma pouch in rats and significant reduction in yeast induced hyperpyrexia in mice. It failed to produce any analgesic activity on the hot plate reaction time test in mice. On the hematological and biochemical parameters it produced a significant prolongation of prothrombin time, a decrease in the fibrinogen content and marked hyperglycemia in rats. It also produced significant neuromuscular blocking activity on both the models used in this study. Apart from these, it exhibited slight inotropic and chronotropic effects on isolated rabbit heart and a mild CNS stimulant effect. Further studies on the isolation of its active phytoconstituents and their pharmacological actions are being undertaken.     

基于抗氧化作用机制的胡黄连苷药理作用研究概况

胡黄连苷（Picroside）是从中药西藏胡黄连中提取的一种天然有效成分,其具有抗氧化、抗炎、调节免疫等作用,已成为目前研究开发的热点。现代医学研究发现,人体各种疾病的发生过程均不同程度地涉及到氧自由基代谢失衡现象。胡黄连苷的相关药理研究已证实其在神经保护、保肝以及抗炎平喘、抗抑郁等领域都具有明显预防或治疗效果,这与其抗氧化作用机制有着密切联系。现就近年来基于抗氧化作用的胡黄连苷在多个领域的相关研究予以概述。     

Structure-activity relationship for antiinflammatory effect of luteolin and its derived glycosides

Luteolin and its derived glycosides such as a cynaroside, cesioside, isoorientin and stereolensin have been isolated and identified from different kinds of plant species. A (13)C NMR spectroscopic analysis of stereolensin has been done for the first time.These structurally related flavonoids were examined in vitro for their abilities to inhibit enzymes for the synthesis of thromboxane B(2) and leukotriene B(4) as well as hydrogen peroxide scavenging activity. Luteolin exhibited a high inhibitory activity against both thromboxane and leukotriene synthesis. In particular, a remarkable inhibitory effect was observed against leukotriene enzyme activity. The glycosides, cynaroside and cesioside, possessed a moderate inhibition activity against both enzyme synthesis pathways, while isoorientin and stereolensin exhibited selectively good activity against thromboxane synthesis.All the flavonoids showed excellent scavenging activity for the hydrogen peroxide at all the concentrations tested.The results demonstrated that the reactivities of luteolin and its related glycosides against arachidonic acid synthesis and hydrogen peroxide scavenging are dependent on their molecular structures. The presence of ortho-dihydroxy groups at the B ring and OH substitution pattern at C-5 position of the A ring could significantly contribute to the antiinflammatory and antioxidant activities of flavonoids.     

The in vitro effects of Hypericum species on human leukocyte myeloperoxidase activity

Myeloperoxidase (MPO) is a major component of the antimicrobial system of polymorphonuclear neutrophils. The heme enzyme MPO catalyzes the conversion of hydrogen peroxide and chloride to hypochlorous acid. Hypochlorous acid is the major strong oxidant produced by neutrophils and may contribute to inflammatory tissue damage. It was reported that certain antiinflammatory drugs are capable of inhibiting MPO activity and this inhibition may account for their antiinflammatory effect. Hypericum L. is a genus of about 400 species, widespread throughout the world. Some species of genus exhibit a significant antiinflammatory activity beside their several pharmacological properties such as antidepressant, diuretic, antihelmintic, and antibacterial. In this study, we investigated the in vitro effects of three Hypericum species, which exhibit antiinflammatory activity, on human polymorphonuclear leukocyte MPO activity. We found that each extract of Hypericum species reduced the peroxidative and chlorinating activity of human leukocyte MPO in concentration-dependent manner. The antiinflammatory activity of these species may be related with inhibition of MPO activity.